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Metabolites May 2021Peroxisomes are central hubs for cell metabolism and their dysfunction is linked to devastating human disorders, such as peroxisomal biogenesis disorders and single...
Peroxisomes are central hubs for cell metabolism and their dysfunction is linked to devastating human disorders, such as peroxisomal biogenesis disorders and single peroxisomal enzyme/protein deficiencies. For decades, biochemical diagnostics have been carried out using classical markers such as very long-chain fatty acids (VLCFA), which can be inconspicuous in milder and atypical cases. Holistic metabolomics studies revealed several potentially new biomarkers for peroxisomal disorders for advanced laboratory diagnostics including atypical cases. However, establishing these new markers is a major challenge in routine diagnostic laboratories. We therefore investigated whether the commercially available AbsoluteIDQ p180 kit (Biocrates Lifesciences), which utilizes flow injection and liquid chromatography mass spectrometry, may be used to reproduce some key results from previous global metabolomics studies. We applied it to serum samples from patients with mutations in peroxisomal target genes , , and the gene. Here we found various changes in sphingomyelins and lysophosphatidylcholines. In conclusion, this kit can be used to carry out extended diagnostics for peroxisomal disorders in routine laboratories, even without access to a metabolomics unit.
PubMed: 34072483
DOI: 10.3390/metabo11060347 -
Molecular Genetics and Metabolism... Sep 2022Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder caused by variants in the gene and can lead to Addison disease, childhood cerebral ALD, or...
BACKGROUND
Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder caused by variants in the gene and can lead to Addison disease, childhood cerebral ALD, or adrenomyeloneuropathy. Presymptomatic hematopoietic stem cell transplantation is the only curative treatment for the disease and requires early detection through newborn screening (NBS) and close follow-up.
METHODS
An NBS program for ALD was performed by a two-tiered dried blood spot (DBS) lysophosphatidylcholine C26:0 (C26:0-LPC) concentration analysis. sequencing was eventually added as a third-tier test, and whole exome sequencing was used to confirm the diagnosis of all peroxisomal diseases. Affected newborns were followed-up for adrenal insufficiency and cerebral white matter abnormalities.
RESULTS
We identified 12 males and 10 females with variants, and 3 patients with Zellweger syndrome from 320,528 newborns. Eight (36.4%) variants identified in the current study were null variants, but there were no hotspots or founder effect. During a median follow-up period of 2.28 years, two (16.7%) male patients with variants developed Addison's disease. Extended family screening revealed one 28-year-old asymptomatic hemizygous father of a null variant (c.678delC). Among the three with Zellweger syndrome, one died at the age of 3 months, one showed developmental delay at the age of 1 year, and one was lost to follow-up.
CONCLUSION
Screening for ALD has been added to the NBS program in Taiwan with a high degree of success. The screening algorithm revealed a high proportion of null variants in cases found by NBS in Taiwan, a subset of patients who may have earlier disease onset. We also demonstrate the feasibility of combining the diagnosis of ALD and other peroxisomal disorders into one screening algorithm.
PubMed: 36046390
DOI: 10.1016/j.ymgmr.2022.100902 -
Frontiers in Cell and Developmental... 2021Peroxisome biogenesis disorders (PBDs) are a group of metabolic developmental diseases caused by mutations in one or more genes encoding peroxisomal proteins. Zellweger...
Peroxisome biogenesis disorders (PBDs) are a group of metabolic developmental diseases caused by mutations in one or more genes encoding peroxisomal proteins. Zellweger syndrome spectrum (PBD-ZSS) results from metabolic dysfunction caused by damaged or non-functional peroxisomes and manifests as a multi-organ syndrome with significant morbidity and mortality for which there is no current drug therapy. Mild PBD-ZSS patients can exhibit a more progressive disease course and could benefit from the identification of drugs to improve the quality of life and extend the lifespan of affected individuals. Our study used a high-throughput screen of FDA-approved compounds to identify compounds that improve peroxisome function and biogenesis in human fibroblast cells carrying the mild PBD-ZSS variant, . Our screen identified the nitrogen oxide donor, -nitrosoglutathione (GSNO), as a potential therapeutic for this mild form of PBD-ZSS. Further biochemical characterization showed that GSNO enhances both peroxisome number and function in mutant fibroblasts and leads to increased survival and longer lifespan in an humanized model carrying the mutation. GSNO is therefore a strong candidate to be translated to clinical trials as a potential therapeutic for mild PBD-ZSS.
PubMed: 34434934
DOI: 10.3389/fcell.2021.714710 -
Bio-protocol Dec 2020Pipecolic acid (Pip), a non-proteinacious product of lysine catabolism, is an important regulator of immunity in plants and humans alike. For instance, Pip accumulation...
Pipecolic acid (Pip), a non-proteinacious product of lysine catabolism, is an important regulator of immunity in plants and humans alike. For instance, Pip accumulation is associated with the genetic disorder Zellweger syndrome, chronic liver diseases, and pyridoxine-dependent epilepsy in humans. In plants, Pip accumulates upon pathogen infection and is required for plant defense. The aminotransferase ALD1 catalyzes biosynthesis of Pip precursor piperideine-2-carboxylic acid, which is converted to Pip via ornithine cyclodeaminase. A variety of methods are used to quantify Pip, and some of these involve use of expensive amino acid analysis kits. Here, we describe a simplified procedure for quantitative analysis of Pip from plant tissues. Pipecolic acid was extracted from leaf tissues along with an internal standard norvaline, derivatized with propyl chloroformate and analyzed by gas chromatography-coupled mass spectrometry using selective ion mode. This procedure is simple, economical, and efficient and does not involve isotopic internal standards or multiple-step derivatizations.
PubMed: 33659490
DOI: 10.21769/BioProtoc.3841 -
Epilepsy & Behavior Reports 2024Zellweger Syndrome is a peroxisomal disorder that can lead to elevation of long chain fatty acids and epilepsy, which can be drug resistant. The treatment of drug...
Zellweger Syndrome is a peroxisomal disorder that can lead to elevation of long chain fatty acids and epilepsy, which can be drug resistant. The treatment of drug resistant epilepsy can include the ketogenic diet in appropriately chosen patients. Typically, the ketogenic diet is contraindicated in individuals with defects in fatty acid metabolism because of the diet's reliance on medium and long chain fatty acids. To our knowledge this is the first publication outlining the use of the ketogenic diet in patients with defects in beta oxidation of very long chain fatty acids. We present two patients with Zellweger Syndrome who were placed on a ketogenic diet for drug resistant epilepsy. Safety and tolerance of the ketogenic diet in patients with Zellweger Syndrome.
PubMed: 38501062
DOI: 10.1016/j.ebr.2024.100655 -
Oxford Medical Case Reports Jun 2024Pigmentary retinal dystrophy (PRD) is a group of inherited disorders involving the progressive degeneration of rod and cone photoreceptors and the retinal pigment...
Pigmentary retinal dystrophy (PRD) is a group of inherited disorders involving the progressive degeneration of rod and cone photoreceptors and the retinal pigment epithelium (RPE), which can progress to pigmentary retinopathy (PR). We present a case of PRD in a female pediatric patient who has pathogenic variants in the PRPH2 and PEX1 genes. The patient has associated macular edema and secondary visual impairment. Treatment has included serial dexamethasone intravitreal implant injections and topical dorzolamide. The PEX1 gene mutation is associated with peroxisome biogenesis disorder-Zellweger syndrome spectrum (PBD-ZSS) and resulting retinal dystrophies. The PRPH2 mutation may play a role in macular edema and PRD, as it is implicated in macular degeneration, choroid defects, and photoreceptor dysfunction. In this case, we review multiple gene mutations playing potential etiologic roles for PRD and discuss care management.
PubMed: 38860019
DOI: 10.1093/omcr/omae067 -
The International Journal of... Jun 2023
Topics: Humans; Takotsubo Cardiomyopathy; Predictive Value of Tests; Heart; Electrocardiography; Acute Coronary Syndrome
PubMed: 36913156
DOI: 10.1007/s10554-023-02813-1 -
Orphanet Journal of Rare Diseases Nov 2023Zellweger spectrum disorders (ZSD) and X-linked adrenoleukodystrophy (X-ALD) are inherited metabolic diseases characterized by dysfunction of peroxisomes, that are...
BACKGROUND
Zellweger spectrum disorders (ZSD) and X-linked adrenoleukodystrophy (X-ALD) are inherited metabolic diseases characterized by dysfunction of peroxisomes, that are essential for lipid metabolism and redox balance. Oxidative stress has been reported to have a significant role in the pathogenesis of neurodegenerative diseases such as peroxisomal disorders, but little is known on the intracellular activation of Mitogen-activated protein kinases (MAPKs). Strictly related to oxidative stress, a correct autophagic machinery is essential to eliminated oxidized proteins and damaged organelles. The aims of the current study are to investigate a possible implication of MAPK pathways and autophagy impairment as markers and putative therapeutic targets in X-ALD and ZSDs.
METHODS
Three patients with ZSD (2 M, 1 F; age range 8-17 years) and five patients with X-ALD (5 M; age range 5- 22 years) were enrolled. A control group included 6 healthy volunteers. To evaluate MAPKs pathway, p-p38 and p-JNK were assessed by western blot analysis on peripheral blood mononuclear cells. LC3II/LC3I ratio was evaluated ad marker of autophagy.
RESULTS
X-ALD and ZSD patients showed elevated p-p38 values on average 2- fold (range 1.21- 2.84) and 3.30-fold (range 1.56- 4.26) higher when compared with controls, respectively. p-JNK expression was on average 12-fold (range 2.20-19.92) and 2.90-fold (range 1.43-4.24) higher in ZSD and X-ALD patients than in controls. All patients had altered autophagic flux as concluded from the reduced LC3II/I ratio.
CONCLUSIONS
In our study X-ALD and ZSD patients present an overactivation of MAPK pathways and an inhibition of autophagy. Considering the absence of successful therapies and the growing interest towards new therapies with antioxidants and autophagy inducers, the identification and validation of biomarkers to monitor optimal dosing and biological efficacy of the treatments is of prime interest.
Topics: Humans; Child; Adolescent; Child, Preschool; Young Adult; Adult; Adrenoleukodystrophy; Zellweger Syndrome; Leukocytes, Mononuclear; Peroxisomes; Oxidation-Reduction
PubMed: 37974207
DOI: 10.1186/s13023-023-02940-x -
Molecular Genetics and Metabolism 2020Sjögren-Larsson syndrome (SLS) is an inherited metabolic disease characterized by ichthyosis, spasticity, intellectual disability and deficient oxidation and...
Sjögren-Larsson syndrome (SLS) is an inherited metabolic disease characterized by ichthyosis, spasticity, intellectual disability and deficient oxidation and accumulation of of fatty aldehydes and alcohols. We investigated whether excess fatty alcohols in SLS are diverted into biosynthesis of ether glycerolipids (eGLs) by measuring the 1-O-alkylglycerol (AG) backbone of eGLs in stratum corneum, plasma and red blood cells (RBCs). In all tissues, saturated and monounsaturated AGs were detected. In stratum corneum from SLS patients, saturated AGs (C15-C20) were increased 97-fold (range: 86- to 169-fold) compared to controls. AGs were largely (67 ± 9%) derived from neutral esterified eGLs (i.e. alkyl-diacylglyerol) and free non-esterified AGs (28 ± 10%), but very little from plasmalogens (3 ± 5%). Plasma from SLS patients had 2-fold more C18:0-AG (p < 0.005) and 40% less C16:1-AG (p < 0.01) than controls but the total concentration of AGs was not increased, and the AG profile in RBCs from SLS subjects was normal. All AGs were profoundly reduced in plasma and RBCs from patients with Zellweger spectrum disorder, who have impaired eGL (i.e. plasmalogen) synthesis. The striking accumulation of AGs in stratum corneum of SLS patients constitutes a novel lipid biomarker for this disease, and may contribute to the pathogenesis of the ichthyosis. Measurement of AGs is a simple and convenient method to assess global synthesis of eGLs and potentially identify patients with defects in their metabolism.
Topics: Aldehydes; Cells, Cultured; Epidermis; Ethers; Fatty Acids; Fatty Alcohols; Female; Fibroblasts; Humans; Ichthyosis; Intellectual Disability; Lipid Metabolism; Male; Muscle Spasticity; Oxidation-Reduction; Sjogren-Larsson Syndrome
PubMed: 32800643
DOI: 10.1016/j.ymgme.2020.08.002 -
EMBO Reports Oct 2021Zellweger spectrum disorder (ZSD) is the most severe peroxisomal biogenesis disorder (PBD). Why ZSD patients not only loose functional peroxisomes but also present with...
Zellweger spectrum disorder (ZSD) is the most severe peroxisomal biogenesis disorder (PBD). Why ZSD patients not only loose functional peroxisomes but also present with severe mitochondrial dysfunction was a long-standing mystery. In this issue, Nuebel et al (2021) identified that loss of peroxisomes leads to re-routing of peroxisomal proteins to mitochondria, thereby impairing mitochondrial structure and function. The findings provide the first molecular understanding of the mitochondrial-peroxisomal link in ZSD.
Topics: Humans; Mitochondria; Peroxins; Peroxisomal Disorders; Peroxisomes; Zellweger Syndrome
PubMed: 34414648
DOI: 10.15252/embr.202153790